ROLE OF PLATELET-ACTIVATING-FACTOR IN HEPATOCELLULAR CA2-SHOCK( ALTERATIONS DURING HEMORRHAGIC)

A role of the potent proinflammatory Ca2+ agonist platelet-activating factor (PAF) on hepatocellular Ca2+ homeostasis and oxidant injury was investigated, since Ca2+ dysregulation has been demonstrated as a piv otal pathomechanism causing hepatic dysfunction during hemorrhagic or septic shock. In anesthetized male Sprague-Dawley rats, blood was with drawn to a mean arterial blood pressure of 40 mm Hg for 60 min. Rats w ere resuscitated with 60% of shed blood and threefold the shed blood v olume of lactated Ringers' (shock group). After 60 min of resuscitatio n, hepatocytes were isolated by portal collagenase perfusion. Hepatoce llular Ca2+ uptake (Ca-up(2+)), initial rate of Ca2+ influx (Ca-in(2+) ), and membrane Ca2+ flux (Ca-flux(2+)) were determined using Ca-45(2) incubation techniques. Hepatocyte oxidant injury was fluorometricall y determined by thiobarbituric acid reactive substances. Ca-up(2+) (3. 37 +/- 0.15 vs. 2.53 +/- 0.08 nmole Ca2+/mg protein), Ca-in(2+) (0.42 +/- 0.1 vs. 0.27 +/- 0.02 nmole Ca2+/mg protein/min), and Ca-flux(2+) (31.3 +/- 4.3 vs. 16.9 +/- 2.4 pmole Ca2+/mg/min) significantly increa sed in the untreated shock group compared to untreated sham-operated r ats (P < 0.05). The specific PAF receptor antagonist BN52021 given 5 m in before (5 mg/kg b.w.) and continuously during resuscitation (5 mg/k g/hr) significantly reduced Ca-up(2+) in the shock group (2.73 +/- 0.2 ; P < 0.01) and prevented hepatocyte lipid peroxidation (shock: 91.9 /- 1; shock(BN52021): 66.7 +/- 2 nmole/mg wet weight; P < 0.01). These data suggest that platelet-activating factor plays a pivotal role in promoting hepatocyte Ca2+ overload during hemorrhagic shock by releasi ng Ca2+ agonistic mediators and inducing oxidative membrane alteration s both of which are capable of enhancing cellular Ca2+ influx. (C) 199 7 Academic Press.